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Driver mutations lung cancer

Tamkin Ahmadzada, Steven Kao, Glen Reid, Michael Boyer, Annabelle Mahar, Wendy A Cooper
It is now widely established that management of lung cancer is much more complex and cannot be centered on the binary classification of small-cell versus non-small cell lung cancer (NSCLC). Lung cancer is now recognized as a highly heterogeneous disease that develops from genetic mutations and gene expression patterns, which initiate uncontrolled cellular growth, proliferation and progression, as well as immune evasion. Accurate biomarker assessment to determine the mutational status of driver mutations such as EGFR , ALK and ROS1 , which can be targeted by specific tyrosine kinase inhibitors, is now essential for treatment decision making in advanced stage NSCLC and has shifted the treatment paradigm of NSCLC to more individualized therapy...
June 15, 2018: Journal of Clinical Medicine
N Daaboul, G Nicholas, S A Laurie
The treatment of squamous non-small-cell lung cancer (nsclc) is evolving. In the past, the backbone of treatment was chemotherapy, with very few other options available. Fortunately, that situation is changing, especially with a better understanding of tumour biology. Various strategies have been tried to improve patient outcomes. The most notable advance must be immunotherapy, which has revolutionized the treatment paradigm for lung cancer in patients without a driver mutation. Immunotherapy is now the treatment of choice in patients who have progressed after chemotherapy and is replacing chemotherapy as upfront therapy in a selected population...
June 2018: Current Oncology
B Melosky
Background: The treatment paradigm for metastatic nonsquamous non-small-cell lung cancer (nsclc) continues to change. Algorithms published only 6 months ago are outdated today and are dramatically different from those published a few years ago. New driver mutations continue to be identified, and the development of therapies to inhibit oncogenic addiction is ongoing. Patient survival is improving as treatments become more personalized and effective. Methods: This review looks at the outcomes of recent trials and discusses treatment options for patients with metastatic nsclc of nonsquamous histology...
June 2018: Current Oncology
G M O'Kane, T A Barnes, N B Leighl
Tumours with sensitizing mutations in the EGFR gene constitute a distinct molecular subgroup of non-small-cell lung cancers (nsclcs) that benefit from precision medicine. First- and second-generation epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) are recommended as upfront therapy for EGFR -mutated advanced nsclc and, compared with chemotherapy, have resulted in superior progression-free survival, improved tumour response rates, and improved quality of life. However, resistance inevitably develops, and the third-generation tki osimertinib has been approved to target the gatekeeper EGFR mutation T790M, which is responsible for resistance in 60% of cases...
June 2018: Current Oncology
Jessie Peh, Matthew W Boudreau, Hannah M Smith, Paul J Hergenrother
The discovery of mutant or fusion kinases that drive oncogenesis, and the subsequent approval of specific inhibitors for these enzymes, has been instrumental in the management of some cancers. However, acquired resistance remains a significant problem in the clinic, limiting the long-term effectiveness of most of these drugs. Here we demonstrate a general strategy to overcome this resistance through drug-induced MEK cleavage (via direct procaspase-3 activation) combined with targeted kinase inhibition. This combination effect is shown to be general across diverse tumor histologies (melanoma, lung cancer, and leukemia) and driver mutations (mutant BRAF or EGFR, fusion kinases EML4-ALK and BCR-ABL)...
May 18, 2018: Cell Chemical Biology
Anju Singh, Christian Ruiz, Kavita Bhalla, John A Haley, Qing Kay Li, George Acquaah-Mensah, Emily Montal, Kuladeep R Sudini, Ferdinandos Skoulidis, Ignacio I Wistuba, Vassiliki Papadimitrakopoulou, John V Heymach, Laszlo G Boros, Edward Gabrielson, Julian Carretero, Kwok-Kin Wong, John D Haley, Shyam Biswal, Geoffrey D Girnun
Oncogenic Kras mutations are one of the most common alterations in non-small cell lung cancer and are associated with poor response to treatment and reduced survival. Driver oncogenes, such as Kras are now appreciated for their ability to promote tumor growth via up-regulation of anabolic pathways. Therefore, we wanted to identify metabolic vulnerabilities in Kras-mutant lung cancer. Using the Kras LSL-G12D lung cancer model, we show that mutant Kras drives a lipogenic gene-expression program. Stable-isotope analysis reveals that mutant Kras promotes de novo fatty acid synthesis in vitro and in vivo...
June 15, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Jan Nyrop Jakobsen, Eric Santoni-Rugiu, Morten Grauslund, Linea Melchior, Jens Benn Sørensen
Background: Patients with EGFR -mutated non-small-cell lung cancer benefit from EGFR tyrosine kinase inhibitors (TKIs) like erlotinib. However, the efficacy may be impaired by driver mutations in other genes. Methods: Five hundred and fourteen consecutive patients with NSCLC of all stages were tested for EGFR -mutations by cobas® EGFR Mutation Test. Fluorescent in situ hybridization (FISH) for MET -amplification, immunohistochemistry (IHC) for MET- and ALK-expression, and Next Generation Sequencing (NGS) for concomitant driver mutations were performed on EGFR -mutated tumor samples from erlotinib-treated patients...
May 25, 2018: Oncotarget
Dianne Hartgerink, Britt van der Heijden, Dirk De Ruysscher, Alida Postma, Linda Ackermans, Ann Hoeben, Monique Anten, Philippe Lambin, Karin Terhaag, Arthur Jochems, Andre Dekker, Janna Schoenmaekers, Lizza Hendriks, Jaap Zindler
Brain metastases (BM) frequently occur in non-small cell lung cancer (NSCLC) patients. Most patients with BM have a limited life expectancy, measured in months. Selected patients may experience a very long progression-free survival, for example, patients with a targetable driver mutation. Traditionally, whole-brain radiotherapy (WBRT) has been the cornerstone of the treatment, but its indication is a matter of debate. A randomized trial has shown that for patients with a poor prognosis, WBRT does not add quality of life (QoL) nor survival over the best supportive care...
2018: Frontiers in Oncology
Stavros Gkolfinopoulos, Giannis Mountzios
Lung cancer remains the leading cause of cancer-related death in men and women, despite its constantly declining rates in incidence and mortality in the developed world. The past decade has witnessed an unprecedented rise in the development of molecular targeted therapies in various types of tumors. In non-small cell lung cancer (NSCLC), the greatest paradigm shift is the implementation of EGFR and ALK tyrosine kinase inhibitors in the first line and subsequent lines of therapy, with impressive results. Though less frequent than the molecular alterations in the aforementioned genes, a number of aberrations in potential oncogenic drivers has been discovered, namely mutations in the genes KRAS , BRAF , HER2 , PI3KCA and DDR2 , ROS1 and RET rearrangements and MET , HER2 and FGFR1 gene amplifications...
April 2018: Annals of Translational Medicine
Panagiota Economopoulou, Giannis Mountzios
Lung cancer remains the leading cause of cancer related death worldwide. Despite broad advances in diagnostics and therapy, the five-year overall survival for patients with advanced non-small cell lung cancer (NSCLC) has not significantly changed over the past few years. Following the decoding of human cancer genome and the advent of therapies targeting driver mutations, the selection of systemic therapy changed from "one size fits all" approach to a more precise selection of biologic therapies targeting distinct genetic profiles...
April 2018: Annals of Translational Medicine
Fangfang Xie, Yujun Zhang, Xiaowei Mao, Xiaoxuan Zheng, Han Han-Zhang, Junyi Ye, Ruiying Zhao, Xueyan Zhang, Jiayuan Sun
OBJECTIVES: Genetic profiles of primary and metastatic lung tumor have been investigated by previous studies. However, whether they can be replaced by each other to guide treatment remains controversial. Moreover, it is unclear that whether genetic profiles of plasma can reflect genetic divergence between primary and metastatic lesions. MATERIALS AND METHODS: In this prospective study, we collected 35 pairs of matched primary tumor tissue, metastatic lymph nodes and plasma from treatment-naïve patients with advanced non-squamous non-small cell lung cancer (NSCLC) and applied to capture-based sequencing using a panel consisting 56 NSCLC-related genes to interrogate the heterogeneity and similarity among the 3 sites...
July 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Naoki Haratake, Mitsuhiro Takenoyama, Makoto Edagawa, Shinichiro Shimamatsu, Ryo Toyozawa, Kaname Nosaki, Fumihiko Hirai, Masafumi Yamaguchi, Kenichi Taguchi, Takashi Seto, Yukito Ichinose
We describe a 77-year-old Japanese woman who presented with three nodule shadows in three different lobes of the right lung, without evidence of lymph node metastasis or distant metastasis. All three tumors were surgically resected. The pathological diagnosis was synchronous multiple primary lung cancer: pT2aN0M0, pStageIB. Based on a differing epidermal growth factor receptor (EGFR) mutation status, no lymph node metastasis, and no distant metastasis, the tumors were characterized as synchronous triple primary rather than intrapulmonary metastases...
April 2018: Journal of Thoracic Disease
Dana Wai Yi Tsui, Muhammed Murtaza, Alvin Seng Cheong Wong, Oscar M Rueda, Christopher G Smith, Dineika Chandrananda, Ross A Soo, Hong Liang Lim, Boon Cher Goh, Carlos Caldas, Tim Forshew, Davina Gale, Wei Liu, James Morris, Francesco Marass, Tim Eisen, Tan Min Chin, Nitzan Rosenfeld
Tumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50 EGFR -mutant non-small-cell lung cancer patients receiving gefitinib and hydroxychloroquine. We performed digital PCR and targeted sequencing on samples from all patients and shallow whole-genome sequencing on samples from three patients who underwent histological transformation to small-cell lung cancer...
May 30, 2018: EMBO Molecular Medicine
Ankur R Parikh, Siraj M Ali, Alexa B Schrock, Lee A Albacker, Vincent A Miller, Phil J Stephens, Pamela Crilley, Maurie Markman
In non-small-cell lung cancer (NSCLC) refractory to standard therapy and which lacks well-known oncogenic drivers, genomic profiling can still identify genomic alterations that may suggest potential sensitivity to targeted therapy. PTEN mutation in NSCLC may be sensitizing to analogs of rapamycin such as everolimus or temsirolimus, but more investigation is needed. We report the case of a patient with metastatic NSCLC harboring a PTEN mutation as well as high tumor mutational burden and PD-L1 positivity with a durable response to temsirolimus, but refractory to a checkpoint inhibitor...
2018: Lung Cancer: Targets and Therapy
Herbert H Loong, Victoria M Raymond, Yukimasa Shiotsu, Daniel T T Chua, Peter M L Teo, Tony Yung, Stan Skrzypczak, Richard B Lanman, Tony S K Mok
BACKGROUND: Genomic profiling of cell-free circulating tumor DNA (ctDNA) is a potential alternative to repeat invasive biopsy in patients with advanced cancer. We report the first real-world cohort of comprehensive genomic assessments of patients with non-small-cell lung cancer (NSCLC) in a Chinese population. PATIENTS AND METHODS: We performed a retrospective analysis of patients with advanced or metastatic NSCLC whose physician requested ctDNA-based genomic profiling using the Guardant360 platform from January 2016 to June 2017...
May 7, 2018: Clinical Lung Cancer
Girish S Shroff, Marcelo F Benveniste, Patricia M de Groot, Brett W Carter, Carol C Wu, Chitra Viswanathan, Mylene T Truong
The identification of genetic mutations known as oncogenic driver mutations that lead to the growth and survival of cancer cells has been an important advance in the field of oncology. Treatment in advanced non-small-cell lung cancer (NSCLC) has transitioned from a more general approach to a more personalized approach based on genetic mutations of the cancer itself. Common mutations detected in patients with advanced NSCLC include mutations of epidermal growth factor receptor and anaplastic lymphoma kinase (ALK)...
June 2018: Seminars in Ultrasound, CT, and MR
Cheng Wang, Rong Yin, Juncheng Dai, Yayun Gu, Shaohua Cui, Hongxia Ma, Zhihong Zhang, Jiaqi Huang, Na Qin, Tao Jiang, Liguo Geng, Meng Zhu, Zhening Pu, Fangzhi Du, Yuzhuo Wang, Jianshui Yang, Liang Chen, Qianghu Wang, Yue Jiang, Lili Dong, Yihong Yao, Guangfu Jin, Zhibin Hu, Liyan Jiang, Lin Xu, Hongbing Shen
Chinese lung cancer patients have distinct epidemiologic and genomic features, highlighting the presence of specific etiologic mechanisms other than smoking. Here, we present a comprehensive genomic landscape of 149 non-small cell lung cancer (NSCLC) cases and identify 15 potential driver genes. We reveal that Chinese patients are specially characterized by not only highly clustered EGFR mutations but a mutational signature (MS3, 33.7%), that is associated with inflammatory tumor-infiltrating B lymphocytes (P = 0...
May 24, 2018: Nature Communications
Claudia Göttlich, Meik Kunz, Cornelia Zapp, Sarah L Nietzer, Heike Walles, Thomas Dandekar, Gudrun Dandekar
Patient-tailored therapy based on tumor drivers is promising for lung cancer treatment. For this we combined in vitro tissue models with in silico analyses. Using individual cell lines with specific mutations we demonstrate a generic and rapid stratification pipeline for targeted tumor therapy. We improve in vitro models of tissue-conditions by a biological matrix-based three-dimensional (3D) tissue culture that allows in vitro drug testing: it correctly shows a strong drug response upon gefitinib treatment in a cell line harboring an EGFR activating mutation (HCC827), but no clear drug response upon treatment with the HSP90 inhibitor 17AAG in two cell lines with KRAS mutations (H441, A549)...
May 24, 2018: Molecular Oncology
Antoine Legras, Marc Barritault, Anne Tallet, Elizabeth Fabre, Alice Guyard, Bastien Rance, William Digan, Nicolas Pecuchet, Etienne Giroux-Leprieur, Catherine Julie, Stéphane Jouveshomme, Véronique Duchatelle, Véronique Giraudet, Laure Gibault, Alain Cazier, Jean Pastre, Françoise LE Pimpec-Barthes, Pierre Laurent-Puig, Hélène Blons
Theranostic assays are based on single gene testing but the ability of next-generation sequencing (NGS) to interrogate numerous genetic alterations will progressively replace single gene assays. Although NGS was evaluated to screen for theranostic mutations, its usefulness in clinical practice on large series of samples remains to be demonstrated. NGS performance was assessed following guidelines. TaqMan probes and NGS were compared for their ability to detect EGFR and KRAS mutations and NGS mutation profiles were analyzed on a large series of NSCLC (n=1,343)...
May 19, 2018: Journal of Molecular Diagnostics: JMD
Mingzhi Ye, Shiyong Li, Weizhe Huang, Chunli Wang, Liping Liu, Jun Liu, Jilong Liu, Hui Pan, Qiuhua Deng, Hailing Tang, Long Jiang, Weizhe Huang, Xi Chen, Di Shao, Zhiyu Peng, Renhua Wu, Jing Zhong, Zhe Wang, Xiaoping Zhang, Karsten Kristiansen, Jian Wang, Ye Yin, Mao Mao, Jianxing He, Wenhua Liang
Background: A non-invasive method to predict the malignancy of surgery-candidate solitary pulmonary nodules (SPN) is urgently needed. Methods: Super-depth next generation sequencing (NGS) of 35 paired tissues and plasma DNA was performed as an attempt to develop an early diagnosis approach. Results: Only ~6% of malignant nodule patients had driver mutations in the circulating tumour DNA (ctDNA) with >10,000-fold sequencing depth, and the concordance of mutation between tDNA and ctDNA was 3...
April 2018: Journal of Thoracic Disease
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